Implantable non-enzymatic electrochemical glucose sensor

ABSTRACT

A non-enzymatic implantable glucose blood detector. The detector makes use of a non-reactive tin oxide semiconductor measurement electrode which is suitably energized by an electrical power source. Variations in current density at the measurement electrode are related to variations in glucose content of blood. The device also uses variable voltage to allow the electrode to be self-cleaning.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to an implantable sensor for making ampherometricmeasurements in body fluids, such as blood or tissue liquid, with ameasurement electrode More specifically, the invention relates to asensor that detects blood glucose levels in vivo and initiates theautomatic dispensing of insulin if detected blood glucose levels exceeda desired set point.

2. Description of the Prior Art

A patient suffering from the metabolic disease diabetes mellitus mustbalance his or her blood sugar level several times daily by injection ofinsulin. In addition, blood sugar controls are required in order toprotect the patient against substantial metabolic deviations. Theseblood sugar controls typically require pricking the patient's finger tipto draw blood, an inconvenience for all patients and a substantialburden for small children and adolescents.

In order to assist in the control of blood sugar, electrochemical enzymesensors have been used to determine blood glucose in vitro. Many ofthese devices, however, are quite expensive and heavy in theirconstruction, such that they can be considered only for stationarytreatment programs.

The use of implantable enzyme sensors has also been proposed. See, e.g.Zier, et al., U.S. Pat. No. 4,919,141. A significant disadvantage ofthese and other enzymatic sensors is that they cannot be usedcontinuously, as they rely on platinum electrodes which react tooquickly with body fluids to offer continuous, long-term service.Consequently, implantable enzyme sensors have a useful life ofrelatively short duration.

Still another disadvantage of prior art sensors is the tendency for themeasurement electrode to become coated with deposits of biologicalmaterials, which impede performance. This problem is especially acute inimplantable units, which become less effective over time as a result ofthe encrustation of the electrode.

Parce et al., U.S. Pat. No. 4,911,794, discloses the use ofsemiconductive electrodes for analyte measurement using a zero volumecell. The patent discloses the use of a number of semiconductiveelectrodes, such as silicon and gallium arsenide, as well as galliumselenide or aluminum gallium arsenide as the working or sensorelectrode. Parce et al. is not, however, concerned with an implantabideunit for measuring blood glucose.

Lerner et al., U.S. Pat. No. 4,340,458, discloses an electrochemicalglucose sensor having a glucose oxidation electrode and aglucose-permeable membrane that separates the electrode from highmolecular weight compounds. The electrodes of this reference areTeflon-bonded platinum and silver/silver-chloride. Neither would beacceptable for an implantable glucose sensor. Obtaining a glucoseconcentration dependent signal by use of a platinum electrode isunreliable non-reproducible and non-specific, as platinum reacts withalmost anything. Furthermore, platinum does not oxidize or reduceglucose, rather oxidizes and reduces phosphate in the presence ofglucose.

Cerami, U.S. Pat. No 4,436,094, discloses a method for continuous, invivo measurement of glucose in body fluids, such as blood, using aglucose monitor including an electrode with a charge-transfer mediumcomprising a reversible complex of a binding micromolecular componentand a charge-bearing carbohydrate component. The electrode is enclosedin a semi-permeable membrane, selectively permeable to glucose.

Bombardineri, U.S. Pat. No. 4,633,878, discloses an implantable devicefor automatic insulin or glucose infusion in diabetic subjects, based onthe continuous monitoring of the patient's glucose levels. The deviceuses an enzymatic-pontentiometric glucose sensor. The reference alsodiscloses the use of hollow fibers, which form a filter through whichonly low molecular weight molecules may pass.

In spite of the above teachings, there is a need for an implantableelectrochemical sensor capable of infusing medicines, such as insulin,when needed.

SUMMARY OF THE INVENTION

The present invention has solved the above noted problems by providing anon-enzymatic blood glucose detector having a non-reactive semiconductormeasurement electrode, preferably tin oxide or titanium dioxide,energized by an electrical power source, such as a battery, and disposedwithin a tubular sleeve comprising a reference electrode and a counterelectrode. The sleeve has an opening therein for permitting glucosemolecules to pass through the sleeve to the measurement electrode, butresist, and preferably preclude the passage of molecules sized greaterthan glucose, preferably greater than about 100,000 M.W., such aslipids, protein, and other large molecules. Amino acids and urea do noteffect the signal of the measurement electrode. The measurementelectrode is connected to a monitoring device for monitoring currentdensity at the measurement electrode, in response to glucose oxidationor glucose reduction reactions taking place at the electrode. Thecurrent density at the measurement electrode is translated into a bloodglucose level by the monitoring device, which may be a microprocessor.

The detector may be an implantable unit adapted for delivering insulinin response to detection by the monitoring device of blood glucoselevels exceeding a predetermined set point. In this case, the unitincludes an insulin reservoir and insulin pump for delivering insulinfrom the reservoir to the patient in response to a signal from themicroprocessor.

It is an object of the invention to provide an implantableelectrochemical sensor that may be used continuously by the patient.

It is another object of the invention to provide a non-enzymaticelectrochemical sensor.

It is still another object of the invention to provide an implantableelectrochemical sensor that may be used over relatively long periods oftime without need of replacement.

It is yet another object of the invention to provide an electrochemicalsensor having a self-cleaning measurement electrode.

It is another object of the invention to provide an implantableelectrochemical sensor that uses a non-reactive but glucose specificmeasurement electrode.

These and other advantages of the invention will become readily apparentas the following detailed description of the preferred embodimentsproceeds, with reference to the illustrations appended hereto.

BRIEF DESCRIPTION OF THE DRAWINGS

A full understanding of the invention can be gained from the followingdescription of the preferred embodiments when read in conjunction withthe accompanying drawings in which:

FIG. 1 is a cross sectional schematic illustration of a preferreddetector of the invention.

FIG. 2 is a cross sectional schematic illustration of another preferreddetector of the invention.

FIG. 3 is a cross sectional schematic illustration of another preferreddetector of the invention.

FIG. 4 is a block circuit diagram of a preferred implantable glucosesensor and insulin delivery system of the invention.

FIG. 5 is a graph illustrating the current density versus glucoseconcentration in blood plasma filtered through a YM100 membrane.

FIG. 6 is a graphical illustration of current density versus time inblood plasma and 80 mg/dL glucose filtered through a YM100 membrane.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used herein, the term "non-reactive semiconductor electrode" means anelectrode formed of a semiconductive material that does not appreciablyreact electrochemically with body fluids, such as blood, over extendedtime periods, such as tin oxide or titanium dioxide.

As used herein, the term "patient" shall be deemed to include humans andanimals.

Referring to FIG. 1, there is shown generally a non-enzymaticelectrochemical sensor 10 having a non-reactive semiconductormeasurement electrode 11, preferably made of tin oxide or titaniumdioxide, which is disposed within a counter electrode, or sleeve, 12. Areference electrode, 17 is also positioned within the sleeve 12. Thesleeve 12, as well as any other implantable component of the inventionhaving direct contact with the body and its fluids, other than themeasurement electrode 11, may be fabricated of any biocompatiblematerial such as stainless steel, titanium, ceramic, etc. Thenon-reactive measurement electrode 11 is energized by an electricalpower source, such as a lithium iodide battery, 2.7 V, in order tosupply a voltage of 1 volt with respect to the reference electrode 17 toprovide a current density at the measurement electrode 11 of about 200to about 500 micro amps/cm².

The sleeve 12 is opened at one end 14, which is covered by abiocompatible membrane 15. This membrane allows glucose molecules toenter the opening 14 in the sleeve 12, where the glucose may be sensedby the non-reactive measurement electrode 11. The membrane 15 is sizedto keep larger molecules, such as those having greater than 100,000molecular weight, for example proteins and lipids, from passing through.These larger molecules would interfere with the measurement being madeby the non-reactive electrode 11. A porous cellulose membrane has beenused as the biocompatible membrane for purposes of the invention. Amongthe preferred materials suitable for use as the membrane 15 arecellulose esters, nylon polyvinyl fluoride, polytetrafluoroethylene,cellulose nitrate, acetate, and mixtures thereof. The membrane is madeof cellulose, supplied, for example, by Micon Co. The preferred membranehas a maximum pore size that allows molecules having less than 100,000dalton (YM 100) through. The other end of the detector 10 is sealed withan insulating ring 16 as illustrated.

FIG. 2 illustrates an alternative embodiment for an electrochemicalsensor 20 having a venturi-type sleeve 22 (counter electrode)surrounding a micro electrode 21. In this embodiment the micro electrode21 is also preferably a semiconductor fabricated of tin oxide ortitanium dioxide. The detector 20 of FIG. 2 has a restricted end 23having a very small opening therein which allows the passagetherethrough of glucose molecules, but which does not allow the passageof molecules larger than 100,000 M.W. A reference electrode 24 is alsopositioned within the sleeve 22 as shown. In this embodiment thecellulose membrane is not required.

In both the embodiments of FIG. 1 and 2 a pump is employed to pump thefluid in and out of the sleeve 22.

The use of a tin oxide or titanium dioxide measurement electrode ascontemplated by the invention allows greater stability for the electrodethan would be possible with, for example, platinum electrodes, whichtend to be too reactive. In contrast, the tin oxide or titanium dioxidesemiconductor measurement electrode of the invention is relativelynon-reactive and therefore can be used continuously and over extendedtime periods.

The electrode surface is preferably about 1 cm², for example, in theform of tin oxide or titanium oxide coated thin wires of 0.2 cm diameterand a length 1.6 cm or 0.4 cm diameter and 0.8 cm long. A thin tin oxideor titanium oxide layer can be put on a platinum or nickel wire by spraypyrolytic deposition using ethanolic 0.1 m tin chloride or 0.1 mtitanium chloride solution at a substrate temperature of 400-°500° C.The carrier gas for the spray solution should be oxygen. Tin oxidecoated glass can also be used as the sensor electrode.

FIG. 3 illustrates another alternative embodiment for a non-enzymaticelectrochemical sensor of the invention. In this embodiment body fluidis not needed to be pumped in and out of the sleeve 33. Rather, bothsides of the sleeve 33 are open and the sensor electrode 30 is locallycovered with a cellulose membrane (YM 100) 30 which allows onlymolecules <100,000 MW to pass through. In FIG. 3, the sensor 31 ispreferably tin oxide or titanium coated platinum or nickel wire. Thereference electrode 32 is also positioned inside the sleeve or counterelectrode 33. The counter electrode 33 may be fabricated of, forexample, titanium. An insulating grid 34 is positioned around the sensorelectrode 31 as illustrated. The sleeve 31 of the FIG. 3 embodiment hastwo open ends 35 and 36, as illustrated.

FIG. 4 illustrates a block circuit diagram for an implantable insulindelivery system of the invention. A patient 51 passes a sample 53, suchas blood, through the detector 55, which screens the larger moleculesand allows the glucose in the blood to pass through and into contactwith the non-reactive electrode contained therein. This electrode, notshown, is energized by a power source, such as a battery, also notshown. The glucose within the sample in the vicinity of the measurementelectrode undergoes an oxidation reaction under applied positivevoltages.

The current density at the non-reactive measurement electrode isproportional to the amount of glucose present in the sample 53, and thiscurrent density can be used as a signal 57 which may be fed to amicroprocessor 60 for comparison to predetermined set points of bloodglucose levels.

The predetermined set point of blood glucose should be about 140 mg/dlof blood. This concentration of glucose will give a signal of about 500micro amps/cm². When this amount of current density is fed into themicroprocessor the microprocessor signals the drug delivery system toinject a fixed amount of drug insulin.

If the microprocessor 60 detects that the signal 57 corresponds to bloodglucose levels exceeding these set points, the microprocessor 60 maysend a signal 62 to an insulin pump/reservoir 64, which canautomatically pump insulin to the patient 51 from a self-containedreservoir. This pumping proceeds until the microprocessor, through loop66, receives a signal that insulin levels have stabilized, at whichpoint the pump is shut down.

The implantable unit can also include a glucose pump and reservoir,adapted to infuse glucose to the patient upon detection of blood sugarlevels below a desired set point.

In a highly preferred embodiment to the invention, the measurementelectrode 11, 21, and 31 is powered with a power source that creates avariable voltage. Preferably, voltages of -0.4 to +1.0 V are used.

The variable voltage can be supplied by a tiny voltage scanner whichcontinuously scans voltage from -0.4 Volt to 1.0 Volt with respect tothe reference electrode (Ag/AgCl) and back again with a scan rate of 200mV/sec.

The variable voltage allows the measurement electrode to beself-cleaning, and thereby avoids problems with prior electrodes, thattend to become encrusted with deposits.

FIG. 5 illustrates that the current density at the measurement electrodeof the invention increases with the increase of glucose concentration inblood. As the concentration of glucose goes above the normalconcentration level by 0 to 160 mg/dL the current density increases from-300 microamps per cm² to -550 microamps per cm². This is an easilydetectable change in current density.

The detector functions by allowing the change in current densityassociated with a change in glucose levels to be measured as a result ofglucose oxidation or reduction reactions occurring at the measurementelectrode, which changes in current density are translated into changesin blood glucose level by the microprocessor 60 (FIG. 4). Typically, apreferred set point for activating the insulin pump 64 would occur ifblood glucose levels of the patient exceed about 150 mg per/dL. This setpoint would, of course, vary from patient to patient.

FIG. 6 shows that no decrease in signal is observed for as long as 480minutes (8 hours) when a tin oxide electrode of the invention is placedin blood plasma, provided that the electrode is covered with a 100,000molecular weight cellulose membrane. This demonstrates the potential forconsistent, long-term use of the invention.

The implantable unit may be implanted in the patient in any number ofways that comprise no part of the invention. For example, it would bepossible to implant the measurement electrode/sleeve assembly in thepatient's podal vein where glucose concentration variation could beeasily monitored, and implant the remainder of the apparatus, such asbattery, insulin pump and microprocessor, within the thoracic cavity ofthe patient.

While specific embodiments of the invention have been described indetail, it will be appreciated by those skilled in The art that variousmodifications and alternatives to those details could be developed inlight of the overall teaching of the disclosure. Accordingly, theparticular arrangements disclosed are meant to be illustrative only andnot limiting as to the scope of the invention, which is to be given thefull breadth of the appended claims and any and all equivalents thereof.Additionally, although a number of objects of the invention have beenrecited herein, it is specifically intended that the claims, and not theobjects, define the scope of the invention.

I claim:
 1. An implantable unit adapted for delivering insulin inresponse to detection of blood glucose levels exceeding a predeterminedset point, said unit comprising a non-reactive semiconductor measurementelectrode, said electrode energized by an electrical power source anddisposed within a sleeve member having an opening permitting glucosemolecules to pass therethrough to said measurement electrode, butresisting the passage therethrough of molecules of predetermined greatersize, said measurement electrode being connected to monitoring means formonitoring current density at said measurement electrode, in response toglucose molecules oxidation or glucose molecules reduction reactions atsaid measurement electrode, said monitored current density beingtranslated into a blood glucose level by said monitoring means, saidunit further including an insulin reservoir and insulin pump fordelivering insulin from said reservoir to a patient in response to asignal from said monitoring means that the blood glucose level of saidpatient has exceeded said set point.
 2. The detector of claim 1, whereinsaid power source creates a continuous variable voltage, therebymaintaining said electrode in a clean state.
 3. The detector of claim 1,wherein said non-reactive semiconductor measurement electrode isfabricated from a semiconductor material selected from the groupconsisting of tin oxide and titanium dioxide.
 4. The detector of claim3, wherein said sleeve member comprises a venturi tube having an openingfor allowing said glucose molecules to pass therethrough but precludespassage therethrough of molecules larger than about 100,000 M.W.
 5. Animplantable unit adapted for delivering insulin in response to detectionof blood glucose levels exceeding a predetermined set point, said unitcomprising a non-reactive semiconductor electrode, said electrodeenergized by an electrical power source and disposed within a sleevemember having an opening covered with a biocompatible membrane having apore size permitting glucose molecules to pass therethrough to saidelectrode, but resisting the passage therethrough of molecules sizedgreater than about 100,000 M.W., said electrode being connected tomonitoring means for monitoring current density at said electrode, inresponse to glucose oxidation or glucose reduction reactions at saidelectrode, said monitored current density being translated into a bloodglucose level by said monitoring means, said unit further including aninsulin reservoir and insulin pump for delivering insulin from saidreservoir to a patient in response to a signal from said monitoringmeans that the blood glucose level of said patient has exceeded said setpoint.
 6. The detector of claim 5, wherein said power source creates acontinuous variable voltage, thereby maintaining said electrode in aclean slate.
 7. The detector of claim 5, wherein said non-reactivesemiconductor electrode is fabricated from a semiconductor materialselected from the group consisting of tin oxide and titanium dioxide.